PHOTOLYSIS OF SULFIRAM - A MECHANISM FOR ITS DISULFIRAM-LIKE REACTION

Sulfiram, a drug applied topically to treat scabies, produces effects similar to those of disulfiram after subsequent ingestion of ethanol. Disulfiram, used in aversion therapy in the treatment of alcoholism, i nhibits hepatic aldehyde dehydrogenase (ALDH) causing an accumulation of acetaldehyde after ethanol ingestion. The increased tissue levels o f acetaldehyde cause a spectrum of undesirable side-effects including flushing, nausea, vomiting, and tachycardia, which are referred to as the disulfiram reaction. Previous studies have shown that in vitro sul firam is a very weak inhibitor of ALDH, but solutions of sulfiram mark edly increase in potency with time. In the present study, fresh soluti ons of sulfiram were exposed to fluorescent room light under ambient c onditions and analyzed at timed intervals by HPLC. At least eight prod ucts, including disulfiram, were formed in the light-exposed sulfiram solutions, but not in solutions kept in the dark. Structural character ization of two of the photolysis products was obtained by on-line micr obore HPLC-mass spectrometry (mu LC-MS) and on-line microbore HPLC-tan dem mass spectrometry (mu LC-MS/MS) using continuous how-liquid second ary ion mass spectrometry (CF-LSIMS) as the primary ionization method. Sulfiram was converted to disulfiram at an initial rate of 0.7%/hr, a nd the formation of disulfiram correlated with the increase in ALDH in hibition in vitro. The results of this investigation show that while s ulfiram is a weak inhibitor of ALDH in vitro, it is readily photoconve rted to disulfiram, a Very potent inhibitor of ALDH, which may explain the adverse reaction to ethanol after sulfiram therapy.